FOXP2

 FOXP2 is a family of forkhead transcription factors, which are part of a larger Forkhead box family of proteins. They play a crucial role in the development of the areas of the brain responsible for language and speech. In the 1990s, a family of individuals called the “KEs”, all of whom suffer from the same speech and language disorder, were discovered to be heterozygous for FOXP2 due to a mutation in one of their chromosomes. It has been suggested that the KEs lacked necessary concentrations of FOXP2 at critical times during their fetal brain development preventing the areas important for speech to develop. Nonfunctional FOXP2 alleles have been found to cause disruption of the striatum, a part of the basal ganglia responsible for speech. Further, spiny neurons within the striatum were found to have increased dendrite lengths and increased synaptic plasticity when FOXP2 mutant alleles were present, possibly causing the speech dysfunction. FOXP2 also has evolutionary implications. Two well-known amino acid substitutions, T303N and N325S appear to be the major substitutions in FOXP2 which separate the speech development patterns of chimpanzees and humans. Mouse models incorporating these mutations in FOXP2 demonstrated dramatically different ultrasonic vocalizations and decreased dopamine concentrations supporting FOXP2s involvement in the basal ganglia. The improper speech development associated with FOXP2 mutations are reminiscent of symptoms associated with autism and highlights a potential new target for therapeutic intervention.

Structure of Monomeric FOXP2
The forkhead domain of FOXP2 assumes unique dimeric and monomeric structures bound to DNA. The monomeric form binds more tightly to DNA and assumes the canonical winged-helix motif present in all the FOX proteins. The structure consists of four alpha helices capped by a two stranded beta sheet. As is present in all FOX proteins, the turn between helices 2 and 3 contains a 3-10 helix. DNA recognition of FOXP2 is mediated by helix 3. Residues Asn 550, Arg 553, His 554, Ser 557, and Leu 558 form strong hydrogen bonding and hydrophobic interactions with the DNA. Additionally, residues Tyr 509, Leu 527, Trp 573 and Tyr 531 also interact from other helices, wedging helix H3 within the major groove of the DNA. Perhaps unsurprisingly, Arg 553 is conserved among all forkhead proteins. In fact, mutation of Arg 533 to a histidine has been linked to the severe congenital speech disorders mentioned previously. Also of note, mutation of Ile 363 to a valine results in reduced binding to DNA and IPEX syndrome a disease causing T-cell dysfunction and subsequent autoimmunity.

Structure of Dimeric FOXP2
A very unique feature of the FOXP2-DNA structure is its ability to form a domain swapped dimer. In the dimeric structure, two monomers exchange helix H3. The dimeric structure is stabilized by complex aromatic interactions involving aromatic residues 507, 509, 531, 534, 538, 540, 541, and 548. In typical FOX family proteins, dimerization is nearly impossible due to the presence of a proline at position 539, effectively preventing helix 2 and three from merging into a single long H3. In FOXP2, this proline is replaced with an alanine, allowing the long helix to form. This feature is present in all FOXP proteins. Interestingly, the mutations Phe371Cys and Phe371Leu are known to cause FOXP dysfunction and speech issues, but residue Phe 371 (Phe 538 here) is only involved in interactions in the FOXP2 dimeric form, highlighting the importance of the dimeric structure. The dimeric structure interacts with the DNA molecule to <scene name='FOXP2/Dimer_second_inter/2'>a far lesser extent than the monomeric form of FOXP2 however. A morph of the domain swapping can be <scene name='FOXP2/Domain_switching_morph/2'> seen here. </StructureSection>

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This article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.